DOCSLIB.ORG

The Rewards and Challenges of Array-Based Karyotyping for Clinical Oncology Applications

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Rewards and Challenges of Array-Based Karyotyping for Clinical Oncology Applications Leukemia (2009) 23, 829–833 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu EDITORIAL The rewards and challenges of array-based karyotyping for clinical oncology applications Leukemia (2009) 23, 829–833; doi:10.1038/leu.2009.24 the arrays used for karyotyping include SOMA (SNP oligonu- cleotide microarrays)7 and CMA (chromosome microarray).8,9 Some consider all platforms to be a type of array comparative Array-based karyotyping is a powerful new technique for genomic hybridization (arrayCGH), whereas others reserve that assessing chromosomal copy number changes that provides term for two-dye methods, and still others who segregate SNP information not previously obtainable by fluorescent in situ arrays because they generate more and different information hybridization (FISH) or conventional cytogeneticsFwhich can than two-dye arrayCGH methods. be both a blessing and a challenge. In this issue, Gunn et al.1 Regardless of the name of the assay or the probe types used, present atypical 11q deletions identified by array-based array-based karyotyping is becoming standard of care for many karyotyping of chronic lymphocytic leukemia (CLL) that may genetic applications and is now on the verge of bursting into be missed by FISH panels used for prognostic stratification of clinical oncology. CLL is an ideal neoplasm to study with copy this disease. Array-based karyotyping is gaining acceptance as a number arrays because (1) the genetic lesions with known clinical tool, and physicians should be prepared to judiciously clinical relevance are chromosomal gains and losses rather interpret results from these platforms. The advantages of array- than balanced translocations and inversions, (2) DNA from a based karyotyping are many and vary somewhat depending on fresh sample is generally available making the analysis more what kind of array is used, but they include high-resolution, straightforward than that for DNA obtained from formalin-fixed genome-wide copy number assessment in one assay; a paraffin-embedded tissue, (3) the tumor burden is known from permanent, numeric result that does not fade over time like the flow cytometry results and can help guide downstream the fluorescent signals of FISH; the ability to karyotype formalin- analysis, (4) the tumor burden tends to be relatively high in the fixed paraffin-embedded tissues and the simultaneous capture of peripheral blood and (5) enrichment for B cells or CLL cells is loss-of-heterozygosity (LOH) status if using a single-nucleotide simple, cost effective and amenable to routine clinical use, polymorphism (SNP)-based array. However, because arrays can which minimizes the effect of ‘normal clone contamination.’ display the genome at high resolution, it is becoming apparent Several groups have recently published manuscripts using copy that the individual molecular lesions identified earlier by FISH number or SNP arrays to study CLL or to validate them for are actually heterogeneous in both genomic length and copy clinical use,5,10–13 and the technique has been successfully number. The clinical meaning of these different subtypes of applied to several solid2–4,14,15 and liquid16–19 tumors. genetic lesions, if any, is yet to be determined. In addition, many In CLL, it is typical to perform a standard FISH panel to genomic changes of uncertain clinical significance are identified determine copy number at key regions of the genome with by these platforms, and there are no standards for reporting such well-established clinical significance, including 6q, 11q, chro- lesions or for archiving them, so that the reports can be amended mosome 12, 13q14 and 17p. In this issue, Gunn et al.1 use a as our knowledge of these lesions evolve. clinically validated array customized to interrogate all known Array-based karyotyping can be carried out with several CLL prognostic loci (179 probes) and 914 FISH-mapped linearly different platforms, both laboratory developed and commercial. distributed clones for whole-genome coverage at an average The arrays themselves can be genome-wide with probes resolution of approximately 2.5 Mb. Their manuscript highlights distributed over the entire genome, or targeted with probes for four atypical 11q deletions. These 11q lesions were considered genomic regions known to be involved in a specific disease or atypical because they did not include the ATM gene, and two of group of diseases, or a combination of both. Furthermore, array- the deletions were missed by the commercial FISH probe used based karyotyping can be carried out with ‘copy number only’ for this locus (11q22.3 Vysis LSI ATM probe, Abbott Molecular, arrays or SNP arrays, which can provide both copy number and Des Plaines, IL, USA). The loss of the ATM tumor suppressor LOH status. The probe types used for ‘copy number only’ arrays gene (TSG), located at 11q22, is often implicated in the include cDNA, BAC clones and oligonucleotides (for example, pathogenesis of CLL. However, it is unlikely to be the sole Agilent (Santa Clara, CA, USA), Nimblegen (Madison, WI, cause of the 11q abnormality, as the minimally deleted region of USA). Commercially available SNP arrays can be solid phase 11q houses other potential candidate TSGs, such as RDX and (Affymetrix, Santa Clara, CA, USA) or bead-based (Illumina, San FDX1 genes,20 and not all CLL patients with deletions of 11q Diego, CA, USA). Some arrays may contain both polymorphic have evidence of an ATM mutation of the remaining allele.21 (SNP-containing) and non-polymorphic (copy number only) Other groups have reported data suggesting that there is a probes, such as the Affymetrix SNP 6.0 array. The actual slightly more telomeric but overlapping region that does not resolution of the virtual karyotype will depend primarily on the include ATM.21–23 This finding was corroborated by Lehmann probe density, the probe performance, the quality of the DNA et al.5 who also observed a second commonly deleted region at and the analysis software. Despite the diversity of platforms, 11q that is telomeric to the ATM gene when they used SNP ultimately they all use genomic DNA from disrupted cells to arrays to karyotype CLL samples. It is postulated that this region recreate a high-resolution karyotype in silico. The end product may harbor another TSG associated with the development of does not yet have a consistent name and has been called virtual CLL, and that concurrent deletion of ATM and this other TSG karyotyping,2,3 digital karyotyping,4 molecular allelokaryotyp- may contribute to a poor prognosis. It is therefore likely that a ing5 and molecular karyotyping.6 Other terms used to describe single FISH probe cannot capture all clinically relevant lesions Editorial 830 at this locus. This article underscores how copy number arrays not only allow us to detect lesions missed by FISH, but also enable us to further refine the break points of 11q deletions and help to determine the clinical relevance, if any, of the subtypes of 11q lesions. Aside from variation in the genomic length of the 11q deletions described by Gunn et al.,1 other types of genetic heterogeneity at clinically relevant loci in CLL have been elucidated by array- based karyotyping. Sargent et al.10 report clinical validation data for a custom CLL oligonucleotide array and highlights length heterogeneity at the 13q14 locus. Patel et al.24 report their clinical validation of a custom CLL BAC array and also underscore the length heterogeneity seen at the 13q14 locus. Ouillette et al.25 used 50 K Affymetrix SNP arrays to subtype 13q14 lesions based on copy number (bi- or mono-alleleic loss) and break points, and they propose a subclassification of 13q14 lesions based on length and gene dose heterogeneity of this locus. Although the lesions detected by FISH have generally been thought of as monolithic, most physicians can readily con- ceptualize length heterogeneity of these deletions. However, Figure 1 Cellular basis of regional heterogeneity seen with array- karyotyping with high resolution using arrays is bringing less based karyotyping. Heterozygous deletions are light blue and easily conceptualized genetic lesions into play, such as copy homozygous deletions are dark blue as depicted within a chromosome neutral LOH (acquired uniparental disomy (UPD)) and regional pair in each cell. (a) Clonal evolution, (b) two separate clones, both scenarios will result in apparent regional copy number heterogeneity copy number heterogeneity. UPD refers to a chromosomal when subjected to array-based karyotyping. region in which both copies of that region are acquired from the same parent, resulting in a copy number of two but with LOH (thus, copy neutral LOH). This can occur through mitotic recombination, chromosome non-dysjunction and loss of one parental chromosome with duplication of the other. Copy neutral LOH can act as the ‘second hit’ of the Knudson two hit hypothesis of tumorigenesis, similar to a deletion, resulting in the removal of the remaining wild-type allele of a TSG.26 Copy neutral LOH is reported to constitute 20–80% of the LOH seen in human cancers, both solid and liquid.16,27–30 Using Affymetrix SNP arrays, Pfeifer et al.12 and Lehmann et al.5 identified copy neutral LOH at clinically relevant loci in CLL. This is noteworthy because conventional cytogenetics, FISH or ‘copy number only’ arrays cannot detect this type of lesion. Array-based karyotyping can also readily detect heterogeneity of copy number state and gene dosage within a particular chromosomal regionFso called ‘regional copy number hetero- geneity.’ For example, a region of 13q14 can be deleted in both chromosomes (homozygous deletion), whereas an adjacent, intervening or overlapping genomic region is deleted in only Figure 2 13q14 regional copy number heterogeneity and efficacy of one chromosome (heterozygous deletion). Figure 1a depicts B-cell enrichment. (a) Single-nucleotide polymorphism (SNP) array- clonal evolution of a disease-associated locus, such as 13q14, based karyotype of the 13q14 locus of a chronic lymphocytic showing a single chromosome pair in each cell.
Load more

Recommended publications
  • Y-Chromosome Short Tandem Repeat, Typing Technology, Locus Information and Allele Frequency in Different Population: a Review
    Vol. 14(27), pp. 2175-2178, 8 July, 2015 DOI:10.5897/AJB2015.14457 Article Number: 2E48C3F54052 ISSN 1684-5315 African Journal of Biotechnology Copyright © 2015 Author(s) retain the copyright of this article http://www.academicjournals.org/AJB Review Y-Chromosome short tandem repeat, typing technology, locus information and allele frequency in different population: A review Muhanned Abdulhasan Kareem1, Ameera Omran Hussein2 and Imad Hadi Hameed2* 1Babylon University, Centre of Environmental Research, Hilla City, Iraq. 2Department of Molecular Biology, Babylon University, Hilla City, Iraq. Received 29 January, 2015; Accepted 29 June, 2015 Chromosome Y microsatellites seem to be ideal markers to delineate differences between human populations. They are transmitted in uniparental and they are very sensitive for genetic drift. This review will highlight the importance of the Y- Chromosome as a tool for tracing human evolution and describes some details of Y-chromosomal short tandem repeat (STR) analysis. Among them are: microsatellites, amplification using polymerase chain reaction (PCR) of STRs, separation and detection and advantages of X-chromosomal microsatellites. Key words: Forensic, population, review, STR, Y- chromosome. INTRODUCTION Microsatellites are DNA regions with repeat units that are microsatellite, but repeats of five (penta-) or six (hexa-) 2 to 7 bp in length or most generally short tandem nucleotides are usually classified as microsatellites as repeats (STRs) or simple sequence repeats (SSRs) well. DNA can be used to study human evolution. (Ellegren, 2000; Imad et al., 2014). The classification of Besides, information from DNA typing is important for the DNA sequences is determined by the length of the medico-legal matters with polymorphisms leading to more core repeat unit and the number of adjacent repeat units.
    [Show full text]
  • Combinatorial Genomic Data Refute the Human Chromosome 2 Evolutionary Fusion and Build a Model of Functional Design for Interstitial Telomeric Repeats
    The Proceedings of the International Conference on Creationism Volume 8 Print Reference: Pages 222-228 Article 32 2018 Combinatorial Genomic Data Refute the Human Chromosome 2 Evolutionary Fusion and Build a Model of Functional Design for Interstitial Telomeric Repeats Jeffrey P. Tomkins Institute for Creation Research Follow this and additional works at: https://digitalcommons.cedarville.edu/icc_proceedings Part of the Biology Commons, and the Genomics Commons DigitalCommons@Cedarville provides a publication platform for fully open access journals, which means that all articles are available on the Internet to all users immediately upon publication. However, the opinions and sentiments expressed by the authors of articles published in our journals do not necessarily indicate the endorsement or reflect the views of DigitalCommons@Cedarville, the Centennial Library, or Cedarville University and its employees. The authors are solely responsible for the content of their work. Please address questions to [email protected]. Browse the contents of this volume of The Proceedings of the International Conference on Creationism. Recommended Citation Tomkins, J.P. 2018. Combinatorial genomic data refute the human chromosome 2 evolutionary fusion and build a model of functional design for interstitial telomeric repeats. In Proceedings of the Eighth International Conference on Creationism, ed. J.H. Whitmore, pp. 222–228. Pittsburgh, Pennsylvania: Creation Science Fellowship. Tomkins, J.P. 2018. Combinatorial genomic data refute the human chromosome 2 evolutionary fusion and build a model of functional design for interstitial telomeric repeats. In Proceedings of the Eighth International Conference on Creationism, ed. J.H. Whitmore, pp. 222–228. Pittsburgh, Pennsylvania: Creation Science Fellowship. COMBINATORIAL GENOMIC DATA REFUTE THE HUMAN CHROMOSOME 2 EVOLUTIONARY FUSION AND BUILD A MODEL OF FUNCTIONAL DESIGN FOR INTERSTITIAL TELOMERIC REPEATS Jeffrey P.
    [Show full text]
  • GENETICS and GENOMICS Ed
    GENETICS AND GENOMICS Ed. Csaba Szalai, PhD GENETICS AND GENOMICS Editor: Csaba Szalai, PhD, university professor Authors: Chapter 1: Valéria László Chapter 2, 3, 4, 6, 7: Sára Tóth Chapter 5: Erna Pap Chapter 8, 9, 10, 11, 12, 13, 14: Csaba Szalai Chapter 15: András Falus and Ferenc Oberfrank Keywords: Mitosis, meiosis, mutations, cytogenetics, epigenetics, Mendelian inheritance, genetics of sex, developmental genetics, stem cell biology, oncogenetics, immunogenetics, human genomics, genomics of complex diseases, genomic methods, population genetics, evolution genetics, pharmacogenomics, nutrigenetics, gene environmental interaction, systems biology, bioethics. Summary The book contains the substance of the lectures and partly of the practices of the subject of ‘Genetics and Genomics’ held in Semmelweis University for medical, pharmacological and dental students. The book does not contain basic genetics and molecular biology, but rather topics from human genetics mainly from medical point of views. Some of the 15 chapters deal with medical genetics, but the chapters also introduce to the basic knowledge of cell division, cytogenetics, epigenetics, developmental genetics, stem cell biology, oncogenetics, immunogenetics, population genetics, evolution genetics, nutrigenetics, and to a relative new subject, the human genomics and its applications for the study of the genomic background of complex diseases, pharmacogenomics and for the investigation of the genome environmental interactions. As genomics belongs to sytems biology, a chapter introduces to basic terms of systems biology, and concentrating on diseases, some examples of the application and utilization of this scientific field are also be shown. The modern human genetics can also be associated with several ethical, social and legal issues. The last chapter of this book deals with these issues.
    [Show full text]
  • Genome-Wide Human SNP Array 6.0
    Data Sheet Genome-Wide Human SNP Array 6.0 Introduction The Genome-Wide Human SNP Array 6.0 contains more than 906,600 single nucleotide polymorphisms (SNPs) and more than 946,000 probes for the detection of copy number variation. SNPs on the array are present on 200 to 1,100 base pairs (bp) Nsp I or Sty I digested fragments in the human genome, and are amplified using the Genome-Wide Human SNP Nsp/Sty Assay Kit 5.0/6.0. This assay, which is also compatible with the SNP Array 5.0, now combines the Nsp and Sty fractions previously assayed on two separate arrays. SNPs on the SNP Array 6.0 were screened in more than 500 distinct samples, including 270 HapMap samples and separate diversity samples. Approximately 482,000 SNPs are derived from the previous-generation Mapping 500K and SNP 5.0 Arrays. The remaining 424,000 SNPs include tag SNP markers derived from the International HapMap Project. These novel markers have better representation of SNPs on chromosomes X and Y, mitochondrial SNPs, SNPs in recombination hotspots, and new SNPs added to the dbSNP database after completion of the GeneChip® Human Mapping 500K Array Set. This array contains a total of 946,000 non-polymorphic copy number probes. These probes—744,000 originally selected for their spacing and 202,000 selected based on known copy number changes reported in the Toronto Database of Genomic Variants (DGV)—enable you to detect de novo copy number changes and perform association studies by genotyping both SNP and known copy number polymorphism (CNP) loci (as The Genome-Wide Human SNP Array 6.0 reported by McCarroll, et al.).
    [Show full text]
  • Microdeletion of the Azfc Locus with High Frequency of Mosaicism 46,XY/47XYY in Cases of Non Obstructive Azoospermia in Eastern Population of India
    Microdeletion of the AZFc locus with high frequency of mosaicism 46,XY/47XYY in cases of non obstructive azoospermia in eastern population of India A.K. Saxena and K. Aniket Department of Pathology/Lab Medicine, Molecular Cytogenetics Laboratory, All India Institute of Medical Sciences, Patna (Bihar), India Corresponding author: A.K. Saxena E-mail: [email protected] Genet. Mol. Res. 18 (2): gmr18349 Received May 07, 2019 Accepted June 06, 2019 Published June 18, 2019 DOI http://dx.doi.org/10.4238/gmr18349 ABSTRACT. The etiopathology of male infertility is highly complex, involving gene - environment interactions to regulate spermatogenesis. Consequently, genetic analysis becomes imperative for cases of non-obstructive azoospermia (NOA) to identify the causative factors. Cases (n = 111) of NOA referred to the cytogenetics and molecular genetics laboratory of the All India Institute of Medical Sciences in -Patna from 2013-2018 were subjected to 1) karyotyping using GTG bandings techniques, 2) fluorescence in situ hybridization (FISH) for the sex determining region (SRY), and 3) PCR based analysis of STS markers based on microdeletion of the Y- chromosome after isolation of genomic DNA from whole blood. A flow cytometer was used for a cell- kinetic and DNA methylation study after incorporation of 5-azacytidine (5- AzaC) (1.0 ug/mL) in lymphocyte culture. PCR products were analyzed on an agarose gel (1.5%) and bands were visualized on Gel Doc after ethidium bromide staining. Chromosomal abnormalities, including structural numerical variations, were observed in 14 of the karyotypes. Eight cases showed a 46,XY/47,XYY i.e. mosaic pattern; two cases 46, XY/45/XO; a single case with 47,XY +16; two cases with 46,X+ ring Y; a single case with 46,XY+dicentric in Genetics and Molecular Research 18 (2): gmr18349 ©FUNPEC-RP www.funpecrp.com.br A.K.
    [Show full text]
  • Analyses of DNA, RNA and Protein
    Analyses of DNA, RNA and Protein What are the early discoveries and technological advances that revolutionized our ability to study human inherited disease? Structure of DNA Central dogma Restriction endonucleases Recombinant DNA technology Cloning Vectors Plasmids Double stranded circular DNA origin of replication selectable marker (antibiotic resistance) 1 or more restriction cutting sites can accommodate DNA fragments 5-10kbp Bacteriophage Lambda Large 25kbp double stranded molecule. Cosmids Can accommodate up to 50kbp of DNA YACs (yeast artificial chromosome Can accommodate up to 1000kbp of DNA BACs (Bacterial artificial chromosome) Can accommodate up to 600 kbp Human genomic plasmid library Also: Phage library YAC library BAC library cDNA library in plasmid Hybridization technology Molecular techniques for Analyzing DNA Southern blotting Detection of gene deletion by Southern blotting Southern blotting can be used to detect large alterations such as Deletions duplications Translocations Point mutations if they alter a restriction enzyme cutting site Quantitative Can be used to analyze large regions of DNA Polymerase Chain Reaction PCR analyses small regions of DNA Sequence of the region must be known to generate primers Not quantitative Advantage of PCR over Southern blotting Fast Sensitive Inexpensive PCR can be used to screen for unknown mutations in small regions of DNA using a variety of approaches, for example: Single strand conformation polymorphism analysis Single strand conformation polymorphism
    [Show full text]
  • A Genetic Map of Chromosome 11 Q. Including the Atopy Locus
    Original Paper EurJ Hum Genet 1995;3:188-194 A.J. Sandforda A Genetic Map of Chromosome M.F. Moffat t* S.E. Danielsa 11 q. Including the Atopy Locus Y. Nakamura'0 GM. Lathropc J.M. Hopkind W.O.CM. Cooksona 1608202 a Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK; b Division of Biochemistry, Abstract Cancer Institute, Tokyo, Japan; Atopy is a common and genetically heterogeneous syndrome c CEPHB, Paris, France; and predisposing to allergic asthma and rhinitis. A locus linked to d Osier Chest Unit, Churchill Hospital, Oxford, UK the atopy phenotype has been shown to be present on chromo­ some llql2-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of Key Words the region, using 15 markers to span approximately 27 cM, Atopy and integrate previously published maps. Under a model of Genetic map maternal inheritance, the atopy locus is placed within a 7-cM Linkage analysis interval between D11S480 and D11S451. The interval con­ Chromosome 11 tains the important candidate gene FCERIB. Introduction The linkage has been replicated in nuclear families [3], and has been independently con­ Atopy is a common familial syndrome firmed in extended Japanese families [4], and which underlies allergic asthma and rhinitis. Dutch asthmatic sib pairs [5]. All these posi­ It is characterised by immunoglobulin E re­ tive linkage results were seen in families with sponses to common aero-allergens such as severe symptomatic atopy. Linkage at this grass pollens or house dust mite. An atopy- locus is made more difficult because it is seen associated phenotype may be defined by mea­ predominately through maternal meioses [3- suring prick skin test responses to these aller­ 7], Linkage is also confounded by a high pop­ gens, by measuring specific IgE responses and ulation prevalence, and low penetrance in ear­ by estimating the total serum IgE.
    [Show full text]
  • Pharmaceutical Compositions Comprising Hydroxychloroquine (HCQ), Curcumin, Piperine/ Bioperine and Uses Thereof in the Medical Field
    (19) TZZ 56_8A_T (11) EP 2 561 868 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.02.2013 Bulletin 2013/09 A61K 31/12 (2006.01) A61K 31/4706 (2006.01) A61K 45/06 (2006.01) A61P 35/00 (2006.01) (21) Application number: 11178638.0 (22) Date of filing: 24.08.2011 (84) Designated Contracting States: (72) Inventor: Van Oosten, Anton Bernhard AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 3920 Lommel (BE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: DeltaPatents B.V. Designated Extension States: Fellenoord 370 BA ME 5611 ZL Eindhoven (NL) (71) Applicant: Van Oosten, Anton Bernhard 3920 Lommel (BE) (54) Pharmaceutical compositions comprising hydroxychloroquine (HCQ), Curcumin, Piperine/ BioPerine and uses thereof in the medical field (57) The present invention concerns a pharmaceuti- of a premalignant plasma cell proliferative disorder like cal composition containing HCQ, curcumin and BioPer- a monoclonal gammopathy of undetermined significance ine/piperine and its application in the medical field. In (MGUS) and/or smoldering (asymptomatic) multiple my- particular, the composition according to the invention can eloma (SMM) and/or Indolent multiple myeloma (IMM) be advantageously employed in the prevention or treat- and/or to cause remission of a cancer arising from a pre- ment of a subject presenting with a proliferative disorder, malignant plasma cell proliferative disorder like multiple to slow the progression of and/or or to cause regression myeloma (MM).
    [Show full text]
  • Glossary/Index
    Glossary 03/08/2004 9:58 AM Page 119 GLOSSARY/INDEX The numbers after each term represent the chapter in which it first appears. additive 2 allele 2 When an allele’s contribution to the variation in a One of two or more alternative forms of a gene; a single phenotype is separately measurable; the independent allele for each gene is inherited separately from each effects of alleles “add up.” Antonym of nonadditive. parent. ADHD/ADD 6 Alzheimer’s disease 5 Attention Deficit Hyperactivity Disorder/Attention A medical disorder causing the loss of memory, rea- Deficit Disorder. Neurobehavioral disorders character- soning, and language abilities. Protein residues called ized by an attention span or ability to concentrate that is plaques and tangles build up and interfere with brain less than expected for a person's age. With ADHD, there function. This disorder usually first appears in persons also is age-inappropriate hyperactivity, impulsive over age sixty-five. Compare to early-onset Alzheimer’s. behavior or lack of inhibition. There are several types of ADHD: a predominantly inattentive subtype, a predomi- amino acids 2 nantly hyperactive-impulsive subtype, and a combined Molecules that are combined to form proteins. subtype. The condition can be cognitive alone or both The sequence of amino acids in a protein, and hence pro- cognitive and behavioral. tein function, is determined by the genetic code. adoption study 4 amnesia 5 A type of research focused on families that include one Loss of memory, temporary or permanent, that can result or more children raised by persons other than their from brain injury, illness, or trauma.
    [Show full text]
  • An Integrated Map of Genetic Variation from 1,092 Human Genomes
    ARTICLE doi:10.1038/nature11632 An integrated map of genetic variation from 1,092 human genomes The 1000 Genomes Project Consortium* By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations. Recent efforts to map human genetic variation by sequencing exomes1 individual genome sequences, to help separate shared variants from and whole genomes2–4 have characterized the vast majority of com- those private to families, for example.
    [Show full text]
  • Chromosome SNP Microarray a New High-Density Allele-Specific Diagnostic Platform
    Chromosome SNP Microarray A New High-density Allele-specific Diagnostic Platform Analysis of submicroscopic genomic changes can pair (allele) targets that have two different forms, revealing which form is present at that locus as well as the number of copies of that detect the cause of congenital anomalies and/or DNA segment. CGH-based arrays cannot detect polymorphic allele learning disabilities. targets (only dosage), resulting in a significant advantage for the SNP array. This advantage is based both on added confirmation of Introduction dosage changes through allele comparisons and the identification of Genetic imbalances are often associated with multiple birth defects, syndrome-associated “copy neutral” contiguous stretches of allele developmental delay, growth retardation, and dysmorphic features. homozygosity. The presence of the latter allows for detection of Standard cytogenetic analysis can identify visible chromosomal uniparental disomy for all chromosomes and, when consanguinity alterations, such as an extra chromosome band, but small deletions is present, it will provide the degree as well as the resulting genomic or duplications in the genome cannot be reliably detected. location of regions of recessive allele risk.5,6 Submicroscopic unbalanced rearrangements have been found in approximately 3% of patients with learning disabilities and mental Increase in Genomic Targets retardation of unknown cause using a set of FISH (fluorescence The initial 262,000 SNP microarray has been upgraded to offer a in situ hybridization) probes that can only target the ends of the much more dense array of 1.8 million genomic targets (marker every chromosomes.1 700 bp).7 The ultra dense array is much more sensitive in identifying extremely small genomic variations and more statistically reliable Advances in molecular cytogenetics further improved the sensitivity due to the large increase in markers through which each variation is of testing through the application of microarray-based comparative detected.
    [Show full text]
  • PAX5 Biallelic Genomic Alterations Define a Novel Subgroup of B-Cell
    Leukemia https://doi.org/10.1038/s41375-019-0430-z ARTICLE Acute lymphoblastic leukemia PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia 1,2,3,4,5 1 3,4,6 1 1 Lorenz Bastian ● Michael P. Schroeder ● Cornelia Eckert ● Cornelia Schlee ● Jutta Ortiz Tanchez ● 1 2,7,8 1 1 Sebastian Kämpf ● Dimitrios L. Wagner ● Veronika Schulze ● Konstandina Isaakidis ● 1,3,4 5 1,3,4 9 1 Juan Lázaro-Navarro ● Sonja Hänzelmann ● Alva Rani James ● Arif Ekici ● Thomas Burmeister ● 1 10 11 3,4,12 13 Stefan Schwartz ● Martin Schrappe ● Martin Horstmann ● Sebastian Vosberg ● Stefan Krebs ● 13 14,15 3,4,12 3,4,16 5 Helmut Blum ● Jochen Hecht ● Philipp A. Greif ● Michael A. Rieger ● Monika Brüggemann ● 3,4,16 1,3,4,5 1,2,3,4,5 Nicola Gökbuget ● Martin Neumann ● Claudia D. Baldus Received: 6 September 2018 / Revised: 29 January 2019 / Accepted: 4 February 2019 © Springer Nature Limited 2019 Abstract Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup (‘PAX5- ’ n = fi 1234567890();,: 1234567890();,: plus , 19) by distinct DNA methylation and gene expression pro les. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B-cell differentiation and tumor suppressor functions.
    [Show full text]